Process of preparing ketones of the cyclopentano hydrophenanthrene series and product



, 2,341,557 PROCESS OF PREPWG KE'EQNJES F CYCLOPENTANO ROPN I. SERIESAND PEODEWT Percy 1.. Julian, Maywood, and .iohn Wayne @oiie. Chicago,Ili., assignors to The Glidden flom pany. Cleveland, Ohio, a corporationof @hio No Drawing. Application November 117, 19 1i, Serial! No. 9,426

9 Ciaims. (Ci. 269?.1)

The present invention relates to certain degradation products of bileacids and acids secured by oxidative degradation of sterols, and moreparticularly relates to diketones of the cyclopentano hydrophenanthreneseries.

The object of the present invention is to pro vide a simpler and cleanerseries of reactions whereby bile acids, or acids secured by oxidativedegradation of sterols, might be converted into diketones. Still anotherobject of this invention is to provide a simple and novel synthesis ofthe corpus luteum hormone. The present method also provides a method forpreparing homologus of the corpus luteum hormone certain of which have aPhysiological activity similar to the corpus luteum hormone. Otherobjects will become apparent to those skilled in the art.

Surprisingly little work has been done with acyl chlorides in thecyclopentanophenanthrene series. We have found that A-3-acetoxy-bisnorcholenic acid is readily converted into a crystallinechloride by the action of thionyl chloride under suitable conditions. A-3-acetoxy-bisnorcholenyl chloride (Formula I) is a useful raw materialin the synthesis of valuable compounds in the cyclopentanophenanthreneseries. It reacts very smoothly, for example, with phenyl zinc chlorideto give A 3-acetoxy-bisnorcholenyl-phenyl ketone. (Formula II) .inalmost quantitative yield.

CH: CH|

CH: CH:

0 Agnew p Thus the treatment of M-S-keto-bisnorcholenyl chloride (m) andM-ii-keto-etio-cholenyl chicride (IV) with aikyl and aryl. compounds ofmic,

cadmium and aluminum yield the corresponding 3-22-(V) and 3-20-(VI)diketones.

CHa 0 CH: H-PI-Cl CHa GH! -Cl CH:

prises subjecting anacid chloride compound of the formula The followingexamples are illustrative of the invention:

Example I cm N To an ether solution of 3.5 grams of methylmagnesiumiodide was added a solution of 3 grams of fused zinc chloride in 200 cc.of anhydrous ether. After 30 minutes stirring, an ether solution of 1.5grams of A -3-keto-bisnorcholenyl chloride (prepared from A-3-keto-bisnorcholenid 1 acid of melting point 252 by treatment with Ithionyl chloride) was added, and the mixture in which N is a groupselected from e class sisting of -COCl and H001 to the action-of anorgano-metallic reagent sestirred at room temperature for four hours.The

lected from the class consisting of alkyl and aryl cooled reactionmixture was shaken with 2% H2804 and ether, and the washed ether layerconcompounds of zinc, cadmium and aluminum.

3. The process for producing ketones of the centrated. Diluting theconcentrate with 2 cc.

acetone caused the separation of crystals melting at 195-200. Byfractional crystallization from acetone there were obtained (1) prismsof the diketone melting at 205-207", (2) needles of an isomer of thediketone melting at 190-191, and (3) general formula 9. low-meltingmixture of isomers. Bio-assay showed positive progestational activity inthe latteri'raction. on. c1: 00 R Example I! A solution containingdimethylcadmium was prepared by adding 7.0 grams anhydrous cadmiumchloride to 150 cc. of an ether solution of methyl-magnesium bromideprepared from 1.3 grams of magnesium and excess methyl bromide. Afterstirring the dimethylcadmium solution for 30 minutes, a benzene solutionof 4.0 grams of the acid chloride prepared from A -3-keto-bisnorwhere ishydrocarbon radical which cholenic acid was added rapidly and themixture prises subjecting an acid 01 the mrmula stirred at 30 C. for sixhours. The ether-benzene CH: solution was washed with cold 2% sulfuricacid, CH 1 00 C] with water, with 5% sodium hydroxide solution, 0H.

and again with water. The solvents were removed by steam distillationand the residue dissolved in a small amount of acetone and allowed 40 tocrystallize, whereupon prisms (melting at 19'7- 200) of the diketoneformed. A lower melting mixture of isomers was secured as a by-product.

This application is a continuation-in-part of application Serial No.388,899, filed April 16, 1941. Having described the invention what isclaimed is:

1. The process of producing diketones of the cyclopentano'hydrophenanthrene series which 5 comprises converting a 3-keto acid ofthe cycloto the action of a compound of the formula R'ZnX in which R isa hydrocarbon radical and X is a halide radical.

4. The process for producing ketones of the general formula Y formulapentano hydrophenanthrene series to the acid chloride, and treating the3-keto acid chloride on, H 00 R, with an organo-metallic reagentselected from cm the class consisting of alkyl and aryl compounds ofcadmium, zinc and aluminum to form the diketone.

2. The process for producing diketones of the CH. M 0 0-- where R is ahydrocarbon radical. which comprises subjecting an acid chloride of theformula q cm tin 00 c1 o OH:

' vv 6 in which M is a group selected from the class consisting of -CORand I 7 noon inwhichR is ahydrocarbon radical, which como the action ofa compound of the formula R'2Cd in which R I represents a hydrocarbon inwhich X is selected from the group consisting radlcaL- of C1- and alkylradicals.

5. Acid chlorides of the 3-keto-cyclopentano 9. The acid chloride of 3keto-A4-5 bisnor hydrophenanthrene series. 4 cholehic acid. t

6. A -3 keto-ter-nor-cholenyl alkvl ketones. 5 PERCY L. JULIAN. 7. M43keto-ter-nor-cholenirl methyl ketones. JOHN WAYNE COLE. 8. Compounds ofthe formula: V

CH3 CH3 0 HC-C-X CH1!

